QUININE SULFATE

6 ADVERSE REACTIONS Most common adverse reactions are a cluster of symptoms called "cinchonism", which occurs to some degree in almost all patients taking quinine: headache, vasodilation and sweating, nausea, tinnitus, hearing impairment, vertigo or dizziness, blurred vision, disturbance in color perception, vomiting, diarrhea, abdominal pain, deafness, blindness, and disturbances in cardiac rhythm or conduction ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or www.lupinpharmaceuticals.com. or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Overall Quinine can adversely affect almost every body system. The most common adverse events associated with quinine use are a cluster of symptoms called "cinchonism", which occurs to some degree in almost all patients taking quinine. Symptoms of mild cinchonism include headache, vasodilation and sweating, nausea, tinnitus, hearing impairment, vertigo or dizziness, blurred vision, and disturbance in color perception. More severe symptoms of cinchonism are vomiting, diarrhea, abdominal pain, deafness, blindness, and disturbances in cardiac rhythm or conduction. Most symptoms of cinchonism are reversible and resolve with discontinuation of quinine. The following ADVERSE REACTIONS have been reported with quinine sulfate. Because these reactions have been reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. General Fever, chills, sweating, flushing, asthenia, lupus-like syndrome, and hypersensitivity reactions. Hematologic Agranulocytosis, hypoprothrombinemia, thrombocytopenia, disseminated intravascular coagulation, hemolytic anemia; hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, petechiae, ecchymosis, hemorrhage, coagulopathy, blackwater fever, leukopenia, neutropenia, pancytopenia, aplastic anemia, and lupus anticoagulant. Neuropsychiatric Headache, diplopia, confusion, altered mental status, seizures, coma, disorientation, tremors, restlessness, ataxia, acute dystonic reaction, aphasia, and suicide. Dermatologic Cutaneous rashes, including urticarial, papular, or scarlatinal rashes, pruritus, bullous dermatitis, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, fixed drug eruption, photosensitivity reactions, allergic contact dermatitis, acral necrosis, and cutaneous vasculitis. Respiratory Asthma, dyspnea, pulmonary edema. Cardiovascular Chest pain, vasodilatation, hypotension, postural hypotension, tachycardia, bradycardia, palpitations, syncope, atrioventricular block, atrial fibrillation, irregular rhythm, unifocal premature ventricular contractions, nodal escape beats, U waves, QT prolongation, ventricular fibrillation, ventricular tachycardia, torsades de pointes, and cardiac arrest. Gastrointestinal Nausea, vomiting, diarrhea, abdominal pain, gastric irritation, and esophagitis. Hepatobiliary Granulomatous hepatitis, hepatitis, jaundice, and abnormal liver function tests. Metabolic Hypoglycemia and anorexia. Musculoskeletal Myalgias and muscle weakness. Renal Hemoglobinuria, renal failure, renal impairment, and acute interstitial nephritis. Special Senses Visual disturbances, including blurred vision with scotomata, sudden loss of vision, photophobia, diplopia, night blindness, diminished visual fields, fixed pupillary dilatation, disturbed color vision, optic neuritis, blindness, vertigo, tinnitus, hearing impairment, and deafness.

4 CONTRAINDICATIONS Quinine sulfate is contraindicated in patients with the following: Prolongation of QT interval ( 4 ) Glucose-6-phosphate dehydrogenase (G6PD) deficiency ( 4 ) Myasthenia gravis ( 4 ) Known hypersensitivity to quinine, mefloquine, or quinidine ( 4 ) Optic neuritis ( 4 ) Quinine sulfate is contraindicated in patients with the following: • Prolonged QT interval. One case of a fatal ventricular arrhythmia was reported in an elderly patient with a prolonged QT interval at baseline, who received quinine sulfate intravenously for P. falciparum malaria [see WARNINGS AND PRECAUTIONS ( 5.3 )]. • Glucose-6-phosphate dehydrogenase (G6PD) deficiency. • Hemolysis can occur in patients with G6PD deficiency receiving quinine. • Known hypersensitivity reactions to quinine. • These include, but are not limited to, the following [see WARNINGS AND PRECAUTIONS ( 5.6 )] : • Thrombocytopenia • Idiopathic thrombocytopenia purpura (ITP) and Thrombotic thrombocytopenic purpura (TTP) • Hemolytic uremic syndrome (HUS) • Blackwater fever (acute intravascular hemolysis, hemoglobinuria, and hemoglobinemia) • Known hypersensitivity to mefloquine or quinidine: cross-sensitivity to quinine has been documented [see WARNINGS AND PRECAUTIONS ( 5.6 )]. • Myasthenia gravis. Quinine has neuromuscular blocking activity, and may exacerbate muscle weakness. • Optic neuritis. Quinine may exacerbate active optic neuritis [see ADVERSE REACTIONS ( 6 )] .

11 DESCRIPTION Quinine sulfate is a cinchona alkaloid chemically described as cinchonan-9-ol, 6'-methoxy-, (8α, 9R)-, sulfate (2:1) (salt), dihydrate with a molecular formula of (C 20 H 24 N 2 O 2 ) 2 •H 2 SO 4 •2H 2 O and a molecular weight of 782.94. The structural formula of quinine sulfate is: Quinine sulfate occurs as a white, crystalline powder that darkens on exposure to light. It is odorless and has a persistent very bitter taste. It is only slightly soluble in water, alcohol, chloroform, and ether. Quinine sulfate capsules USP are supplied for oral administration as capsules containing 324 mg of the active ingredient quinine sulfate USP, equivalent to 269 mg free base. Inactive ingredients: black iron oxide, corn starch, gelatin, magnesium stearate, potassium hydroxide, propylene glycol shellac, sodium lauryl sulfate, and talc. 1

2 DOSAGE AND ADMINISTRATION Adults (≥ 16 years of age): 648 mg (two capsules) every 8 hours for 7 days ( 2.1 ). Patients with severe chronic renal impairment: one loading dose of 648 mg (two capsules) followed 12 hours later by 324 mg (one capsule) every 12 hours for 7 days ( 2.2 ). 2.1 Treatment of Uncomplicated P. falciparum Malaria For treatment of uncomplicated P. falciparum malaria in adults: Orally, 648 mg (two capsules) every 8 hours for 7 days [see CLINICAL STUDIES ( 14 )] . Quinine sulfate capsules USP should be taken with food to minimize gastric upset [see CLINICAL PHARMACOLOGY ( 12.3 )] . 2.2 Renal Impairment In patients with acute uncomplicated malaria and severe chronic renal impairment, the following dosage regimen is recommended: one loading dose of 648 mg quinine sulfate capsules USP followed 12 hours later by maintenance doses of 324 mg every 12 hours. The effects of mild and moderate renal impairment on the safety and pharmacokinetics of quinine sulfate are not known [see USE IN SPECIFIC POPULATIONS ( 8.6 ), CLINICAL PHARMACOLOGY ( 12.3 )] . 2.3 Hepatic Impairment Adjustment of the recommended dose is not required in mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, but patients should be monitored closely for adverse effects of quinine. Quinine should not be administered in patients with severe (Child-Pugh C) hepatic impairment [see USE IN SPECIFIC POPULATIONS ( 8.7 ), CLINICAL PHARMACOLOGY ( 12.3 )] .

1 INDICATIONS AND USAGE Quinine sulfate capsule USP is a cinchona alkaloid indicated for treatment of uncomplicated Plasmodium falciparum malaria ( 1 ). Quinine sulfate capsule USP is an antimalarial drug indicated only for treatment of uncomplicated Plasmodium falciparum malaria. Quinine sulfate has been shown to be effective in geographical regions where resistance to chloroquine has been documented [see CLINICAL STUDIES ( 14 )] . Quinine sulfate capsules USP are not approved for: Treatment of severe or complicated P. falciparum malaria. Prevention of malaria. Treatment or prevention of nocturnal leg cramps [see WARNINGS AND PRECAUTIONS ( 5.1 )] .

10 OVERDOSAGE Quinine overdose can be associated with serious complications, including visual impairment, hypoglycemia, cardiac arrhythmias, and death. Visual impairment can range from blurred vision and defective color perception, to visual field constriction and permanent blindness. Cinchonism occurs in virtually all patients with quinine overdose. Symptoms range from headache, nausea, vomiting, abdominal pain, diarrhea, tinnitus, vertigo, hearing impairment, sweating, flushing, and blurred vision, to deafness, blindness, serious cardiac arrhythmias, hypotension, and circulatory collapse. Central nervous system toxicity (drowsiness, disturbances of consciousness, ataxia, convulsions, respiratory depression and coma) has also been reported with quinine overdose, as well as pulmonary edema and adult respiratory distress syndrome. Most toxic reactions are dose-related; however, some reactions may be idiosyncratic because of the variable sensitivity of patients to the toxic effects of quinine. A lethal dose of quinine has not been clearly defined, but fatalities have been reported after the ingestion of 2 to 8 grams in adults. Quinine, like quinidine, has Class I antiarrhythmic properties. The cardiotoxicity of quinine is due to its negative inotropic action, and to its effect on cardiac conduction, resulting in decreased rates of depolarization and conduction, and increased action potential and effective refractory period. ECG changes observed with quinine overdose include sinus tachycardia, PR prolongation, T wave inversion, bundle branch block, an increased QT interval, and a widening of the QRS complex. Quinine's alpha-blocking properties may result in hypotension and further exacerbate myocardial depression by decreasing coronary perfusion. Quinine overdose has been also associated with hypotension, cardiogenic shock, and circulatory collapse, ventricular arrhythmias, including ventricular tachycardia, ventricular fibrillation, idioventricular rhythm, and torsades de pointes, as well as bradycardia, and atrioventricular block [see WARNINGS AND PRECAUTIONS ( 5 ), CLINICAL PHARMACOLOGY ( 12.3 )] . Quinine is rapidly absorbed, and attempts to remove residual quinine sulfate from the stomach by gastric lavage may not be effective. Multiple-dose activated charcoal has been shown to decrease plasma quinine concentrations [see CLINICAL PHARMACOLOGY ( 12.3 )] . Forced acid diuresis, hemodialysis, charcoal column hemoperfusion, and plasma exchange were not found to be effective in significantly increasing quinine elimination in a series of 16 patients.

7 DRUG INTERACTIONS Interacting Drug Interaction Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents). Quinine sulfate prolongs QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use ( 5.3 ). Other antimalarials (e.g., halofantrine, mefloquine). ECG abnormalities including QT prolongation Avoid concomitant use ( 5.3 , 7.2 ). CYP3A4 inducers or inhibitors Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine ( 7.1 ). CYP3A4 and CYP2D6 substrates Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug ( 7.2 ). Digoxin Increased digoxin plasma concentration ( 5.8 , 7.1 ). See full prescribing information for a complete list of reported and potential interactions. 7.1 Effects of Drugs and Other Substances on Quinine Pharmacokinetics Quinine is a P-gp substrate and is primarily metabolized by CYP3A4. Other enzymes, including CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1 may contribute to the metabolism of quinine [see CLINICAL PHARMACOLOGY ( 12.3 )] . Antacids Antacids containing aluminum and/or magnesium may delay or decrease absorption of quinine. Concomitant administration of these antacids with quinine sulfate should be avoided. Antiepileptics (AEDs) (Carbamazepine, Phenobarbital, and Phenytoin) Carbamazepine, phenobarbital, and phenytoin are CYP3A4 inducers and may decrease quinine plasma concentrations if used concurrently with quinine sulfate. Cholestyramine In 8 healthy subjects who received quinine sulfate 600 mg with or without 8 grams of cholestyramine resin, no significant difference in quinine pharmacokinetic parameters was seen. Cigarette Smoking (CYP1A2 Inducer) In healthy male heavy smokers, the mean quinine AUC following a single 600 mg dose was 44% lower, the mean C max was 18% lower, and the elimination half-life was shorter (7.5 hours versus 12 hours) than in their non-smoking counterparts. However, in malaria patients who received the full 7-day course of quinine therapy, cigarette smoking produced only a 25% decrease in median quinine AUC and a 16.5% decrease in median C max , suggesting that the already reduced clearance of quinine in acute malaria could have diminished the metabolic induction effect of smoking. Because smoking did not appear to influence the therapeutic outcome in malaria patients, it is not necessary to increase the dose of quinine in the treatment of acute malaria in heavy cigarette smokers. Grapefruit Juice (P-gp/CYP3A4 Inhibitor) In a pharmacokinetic study involving 10 healthy subjects, the administration of a single 600 mg dose of quinine sulfate with grapefruit juice (full-strength or half-strength) did not significantly alter the pharmacokinetic parameters of quinine. Quinine sulfate may be taken with grapefruit juice. Histamine H 2 -Receptor Blockers [Cimetidine, Ranitidine (Nonspecific CYP450 Inhibitors)] In healthy subjects who were given a single oral 600 mg dose of quinine sulfate after pretreatment with cimetidine (200 mg three times daily and 400 mg at bedtime for 7 days) or ranitidine (150 mg twice daily for 7 days), the apparent oral clearance of quinine decreased and the mean elimination half-life increased significantly when given with cimetidine but not with ranitidine. Compared to untreated controls, the mean AUC of quinine increased by 20% with ranitidine and by 42% with cimetidine (p<0.05) without a significant change in mean quinine C max . When quinine is to be given concomitantly with a histamine H 2 -receptor blocker, the use of ranitidine is preferred over cimetidine. Although cimetidine and ranitidine may be used concomitantly with quinine sulfate, patients should be monitored closely for adverse events associated with quinine. Isoniazid Isoniazid 300 mg/day pretreatment for 1 week did not significantly alter the pharmacokinetic parameter values of quinine. Adjustment of quinine sulfate dosage is not necessary when isoniazid is given concomitantly. Ketoconazole (CYP3A4 Inhibitor) In a crossover study, healthy subjects (N=9) who received a single oral dose of quinine hydrochloride (500 mg) concomitantly with ketoconazole (100 mg twice daily for 3 days) had a mean quinine AUC that was higher by 45% and a mean oral clearance of quinine that was 31% lower than after receiving quinine alone. Although no change in the quinine sulfate dosage regimen is necessary with concomitant ketoconazole, patients should be monitored closely for adverse reactions associated with quinine. Macrolide Antibiotics (Erythromycin, Troleandomycin) (CYP3A4 Inhibitors) In a crossover study (N=10), healthy subjects who received a single oral 600 mg dose of quinine sulfate with the macrolide antibiotic, troleandomycin (500 mg every 8 hours) exhibited a 87% higher mean quinine AUC, a 45% lower mean oral clearance of quinine, and a 81% lower formation clearance of the main metabolite, 3-hydroxyquinine, than when quinine was given alone. Erythromycin was shown to inhibit the in vitro metabolism of quinine in human liver microsomes, an observation confirmed by an in vivo interaction study. In a crossover study (N=10), healthy subjects who received a single oral 500 mg dose of quinine sulfate with erythromycin (600 mg every 8 hours for four days) showed a decrease in quinine oral clearance (CL/F), an increase in half-life, and a decreased metabolite (3-hydroxyquinine) to quinine AUC ratio, as compared to when quinine was given with placebo. Therefore, concomitant administration of macrolide antibiotics such as erythromycin or troleandomycin with quinine sulfate should be avoided [see WARNINGS AND PRECAUTIONS ( 5.3 )] . Oral Contraceptives (Estrogen, Progestin) In 7 healthy females who were using single-ingredient progestin or combination estrogen-containing oral contraceptives, the pharmacokinetic parameters of a single 600 mg dose of quinine sulfate were not altered in comparison to those observed in 7 age-matched female control subjects not using oral contraceptives. Rifampin (CYP3A4 Inducer) In patients with uncomplicated P. falciparum malaria who received quinine sulfate 10 mg/kg concomitantly with rifampin 15 mg/kg/day for 7 days (N=29), the median AUC of quinine between days 3 and 7 of therapy was 75% lower as compared to those who received quinine monotherapy. In healthy subjects (N=9) who received a single oral 600 mg dose of quinine sulfate after 2 weeks of pretreatment with rifampin 600 mg/day, the mean quinine AUC and C max decreased by 85% and 55%, respectively. Therefore the concomitant administration of rifampin with quinine sulfate should be avoided [see WARNINGS AND PRECAUTIONS ( 5.4 )] . Ritonavir In healthy subjects who received a single oral 600 mg dose of quinine sulfate with the 15 th dose of ritonavir (200 mg every 12 hours for 9 days), there were 4-fold increases in the mean quinine AUC and C max , and an increase in the mean elimination half-life (13.4 hours versus 11.2 hours), compared to when quinine was given alone. Therefore, the concomitant administration of ritonavir with quinine sulfate capsules should be avoided [see also DRUG INTERACTIONS ( 7.2 )] . Tetracycline In 8 patients with acute uncomplicated P. falciparum malaria who were treated with oral quinine sulfate (600 mg every 8 hours for 7 days) in combination with oral tetracycline (250 mg every 6 hours for 7 days), the mean plasma quinine concentrations were about two-fold higher than in 8 patients who received quinine monotherapy. Although tetracycline may be concomitantly administered with quinine sulfate, patients should be monitored closely for adverse reactions associated with quinine sulfate. Theophylline or Aminophylline In 20 healthy subjects who received multiple doses of quinine sulfate (648 mg every 8 hours x 7 days) with a single 300 mg oral dose of theophylline, the quinine mean C max and AUC were increased by 13% and 14% respectively. Although no change in the quinine sulfate dosage regimen is necessary with concomitant theophylline or aminophylline, patients should be monitored closely for adverse reactions associated with quinine. Urinary Alkalizers (Acetazolamide, Sodium Bicarbonate) Urinary alkalinizing agents may increase plasma quinine concentrations. 7.2 Effects of Quinine on the Pharmacokinetics of Other Drugs Results of in vivo drug interaction studies suggest that quinine has the potential to inhibit the metabolism of drugs that are substrates of CYP3A4 and CYP2D6. Quinine inhibits P-gp and has the potential to affect the transport of drugs that are P-gp substrates. Anticonvulsants (Carbamazepine, Phenobarbital, and Phenytoin) A single 600 mg oral dose of quinine sulfate increased the mean plasma C max , and AUC 0–24 of single oral doses of carbamazepine (200 mg) and phenobarbital (120 mg) but not phenytoin (200 mg) in 8 healthy subjects. The mean AUC increases of carbamazepine, phenobarbital and phenytoin were 104%, 81% and 4%, respectively; the mean increases in C max were 56%, 53%, and 4%, respectively. Mean urinary recoveries of the three antiepileptics over 24 hours were also profoundly increased by quinine. If concomitant administration with carbamazepine or phenobarbital cannot be avoided, frequent monitoring of anticonvulsant drug concentrations is recommended. Additionally, patients should be monitored closely for adverse reactions associated with these anticonvulsants. Astemizole (CYP3A4 Substrate) Elevated plasma astemizole concentrations were reported in a subject who experienced torsades de pointes after receiving three doses of quinine sulfate for nocturnal leg cramps concomitantly with chronic astemizole 10 mg/day. The concurrent use of quinine sulfate with astemizole and other CYP3A4 substrates with QT prolongation potential (e.g., cisapride, terfenadine, halofantrine, pimozide and quinidine ) should also be avoided [see WARNINGS AND PRECAUTIONS ( 5.3 )] . Atorvastatin (CYP3A4 Substrate) Rhabdomyolysis with acute renal failure secondary to myoglobinuria was reported in a patient taking atorvastatin administered with a single dose of quinine. Quinine may increase plasma concentrations of atorvastatin, thereby increasing the risk of myopathy or rhabdomyolysis. Thus, clinicians considering combined therapy of quinine sulfate with atorvastatin or other HMG-CoA reductase inhibitors ("statins") that are CYP3A4 substrates (e.g., simvastatin, lovastatin) should carefully weigh the potential benefits and risks of each medication. If quinine sulfate is used concomitantly with any of these statins, lower starting and maintenance doses of the statin should be considered. Patients should also be monitored closely for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy. If marked creatine phosphokinase (CPK) elevation occurs or myopathy (defined as muscle aches or muscle weakness in conjunction with CPK values >10 times the upper limit of normal) is diagnosed or suspected, atorvastatin or other statin should be discontinued. Desipramine (CYP2D6 Substrate) Quinine (750 mg/day for 2 days) decreased the metabolism of desipramine in patients who were extensive CYP2D6 metabolizers, but had no effect in patients who were poor CYP2D6 metabolizers. Lower doses (80 mg to 400 mg) of quinine did not significantly affect the pharmacokinetics of other CYP2D6 substrates, namely, debrisoquine, dextromethorphan, and methoxyphenamine. Although clinical drug interaction studies have not been performed, antimalarial doses (greater than or equal to 600 mg) of quinine may inhibit the metabolism of other drugs that are CYP2D6 substrates (e.g., flecainide, debrisoquine, dextromethorphan, metoprolol, paroxetine ). Patients taking medications that are CYP2D6 substrates with quinine sulfate should be monitored closely for adverse reactions associated with these medications. Digoxin (P-gp Substrate) In 4 healthy subjects who received digoxin (0.5 to 0.75 mg/day) during treatment with quinine (750 mg/day), a 33% increase in mean steady state AUC of digoxin and a 35% reduction in the steady state biliary clearance of digoxin were observed compared to digoxin alone. Thus, if quinine sulfate is administered to patients receiving digoxin, plasma digoxin concentrations should be closely monitored, and the digoxin dose adjusted, as necessary [see WARNINGS AND PRECAUTIONS ( 5.7 )] . Halofantrine Although not studied clinically, quinine was shown to inhibit the metabolism of halofantrine in vitro using human liver microsomes. Therefore, concomitant administration of quinine sulfate is likely to increase plasma halofantrine concentrations [see WARNINGS AND PRECAUTIONS ( 5.3 )] . Mefloquine In 7 healthy subjects who received mefloquine (750 mg) at 24 hours before an oral 600 mg dose of quinine sulfate, the AUC of mefloquine was increased by 22% compared to mefloquine alone. In this study, the QTc interval was significantly prolonged in the subjects who received mefloquine and quinine sulfate 24 hours apart. The concomitant administration of mefloquine and quinine sulfate may produce electrocardiographic abnormalities (including QTc prolongation) and may increase the risk of seizures [see WARNINGS AND PRECAUTIONS ( 5.3 )] . Midazolam (CYP3A4 Substrate) In 23 healthy subjects who received multiple doses of quinine sulfate capsules, 324 mg three times daily x 7 days with a single oral 2 mg dose of midazolam, the mean AUC and C max of midazolam and 1-hydroxymidazolam were not significantly affected. This finding indicates that 7-day dosing with quinine sulfate capsules,324 mg every 8 hours did not induce the metabolism of midazolam. Neuromuscular Blocking Agents (Pancuronium, Succinylcholine, Tubocurarine) In one report, quinine potentiated neuromuscular blockade in a patient who received pancuronium during an operative procedure, and subsequently (3 hours after receiving pancuronium) received quinine 1800 mg daily. Quinine may also enhance the neuromuscular blocking effects of succinylcholine and tubocurarine [see WARNINGS AND PRECAUTIONS ( 5.5 )] . Ritonavir In healthy subjects who received a single oral 600 mg dose of quinine sulfate with the 15 th dose of ritonavir (200 mg every 12 hours for 9 days), the mean ritonavir AUC, C max , and elimination half-life were slightly but not significantly increased compared to when ritonavir was given alone. However, due to the significant effect of ritonavir on quinine pharmacokinetics, the concomitant administration of quinine sulfate capsules with ritonavir should be avoided [see also DRUG INTERACTIONS ( 7.1 )] . Theophylline or Aminophylline (CYP1A2 Substrate) In 19 healthy subjects who received multiple doses of quinine sulfate 648 mg every 8 hours x 7 days with a single 300 mg oral dose of theophylline, the mean theophylline AUC was 10% lower than when theophylline was given alone. There was no significant effect on mean theophylline C max . Therefore, if quinine sulfate is co-administered to patients receiving theophylline or aminophylline, plasma theophylline concentrations should be monitored frequently to ensure therapeutic concentrations. Warfarin and oral anticoagulants Cinchona alkaloids, including quinine, may have the potential to depress hepatic enzyme synthesis of vitamin K-dependent coagulation pathway proteins and may enhance the action of warfarin and other oral anticoagulants. Quinine may also interfere with the anticoagulant effect of heparin. Thus, in patients receiving these anticoagulants, the prothrombin time (PT), partial thromboplastin time (PTT), or international normalization ratio (INR) should be closely monitored as appropriate, during concurrent therapy with quinine sulfate. 7.3 Drug/Laboratory Interactions Quinine may produce an elevated value for urinary 17-ketogenic steroids when the Zimmerman method is used. Quinine may interfere with urine qualitative dipstick protein assays as well as quantitative methods (e.g., pyrogallol red-molybdate).

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Quinine is an antimalarial agent [see CLINICAL PHARMACOLOGY ( 12.4 )] . 12.2 Pharmacodynamics QTc interval prolongation was studied in a double-blind, multiple dose, placebo- and positive-controlled crossover study in young (N=13, 20 to 39 years) and elderly (N=13, 65 to 78 years) subjects. After 7 days of dosing with quinine sulfate 648 mg three times daily, the maximum mean (95% upper confidence bound) differences in QTcI from placebo after baseline correction was 27.7 (32.2) ms. Prolongation of the PR and QRS interval was also noted in subjects receiving quinine sulfate. The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline-correction was 14.5 (18.0) ms. The maximum mean (95% upper confidence bound) difference in QRS from placebo after baseline-correction was 11.5 (13.3) ms. [see WARNINGS AND PRECAUTIONS ( 5.3 )] . 12.3 Pharmacokinetics Absorption The oral bioavailability of quinine is 76 to 88% in healthy adults. Quinine exposure is higher in patients with malaria than in healthy subjects. After a single oral dose of quinine sulfate, the mean quinine T max was longer, and mean AUC and C max were higher in patients with uncomplicated P. falciparum malaria than in healthy subjects, as shown in Table 1 below. TABLE 1 Pharmacokinetic Parameters of Quinine in Healthy Subjects and Patients with Uncomplicated P. falciparum Malaria after a Single Dose Quinine Sulfate dose was 648 mg (approximately 8.7 mg/kg) in healthy subjects; and 10 mg/kg in patients with malaria of Oral Quinine Sulfate Capsules Healthy Subjects ( N = 23 ) Mean ± SD Uncomplicated P . falciparum Malaria Patients ( N = 15 ) Mean ± SD Dose (mg/kg) 8.7 10 T m a x (h) 2.8 ± 0.8 5.9 ± 4.7 C m a x (mcg/mL) 3.2 ± 0.7 8.4 AUC0–12 (mcg*h/mL) 28.0 73.0 Quinine sulfate capsules may be administered without regard to meals. When a single oral 324 mg capsule of quinine sulfate was administered to healthy subjects (N=26) with a standardized high-fat breakfast, the mean T max of quinine was prolonged to about 4.0 hours, but the mean C max and AUC 0-24h were similar to those achieved when quinine sulfate capsule was given under fasted conditions [see DOSAGE AND ADMINISTRATION ( 2.1 )] . Distribution In patients with malaria, the volume of distribution (Vd/F) decreases in proportion to the severity of the infection. In published studies with healthy subjects who received a single oral 600 mg dose of quinine sulfate, the mean Vd/F ranged from 2.5 to 7.1 L/kg. Quinine is moderately protein-bound in blood in healthy subjects, ranging from 69 to 92%. During active malarial infection, protein binding of quinine is increased to 78 to 95%, corresponding to the increase in α 1 -acid glycoprotein that occurs with malaria infection. Intra-erythrocytic levels of quinine are approximately 30 to 50% of the plasma concentration. Quinine penetrates relatively poorly into the cerebrospinal fluid (CSF) in patients with cerebral malaria, with CSF concentration approximately 2 to 7% of plasma concentration. In one study, quinine concentrations in placental cord blood and breast milk were approximately 32% and 31%, respectively, of quinine concentrations in maternal plasma. The estimated total dose of quinine secreted into breast milk was less than 2 to 3 mg per day [see USE IN SPECIFIC POPULATIONS ( 8.1 , 8.3 )] . Metabolism Quinine is metabolized almost exclusively via hepatic oxidative cytochrome P450 (CYP) pathways, resulting in four primary metabolites, 3-hydroxyquinine, 2´-quinone, O -desmethylquinine, and 10,11-dihydroxydihydroquinine. Six secondary metabolites result from further biotransformation of the primary metabolites. The major metabolite, 3-hydroxyquinine, is less active than the parent drug. In vitro studies using human liver microsomes and recombinant P450 enzymes have shown that quinine is metabolized mainly by CYP3A4. Depending on the in vitro experimental conditions, other enzymes, including CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1 were shown to have some role in the metabolism of quinine. Elimination/Excretion Quinine is eliminated primarily via hepatic biotransformation. Approximately 20% of quinine is excreted unchanged in urine. Because quinine is reabsorbed when the urine is alkaline, renal excretion of the drug is twice as rapid when the urine is acidic than when it is alkaline. In various published studies, healthy subjects who received a single oral 600 mg dose of quinine sulfate exhibited a mean plasma clearance ranging from 0.08 to 0.47 L/h/kg (median value: 0.17 L/h/kg) with a mean plasma elimination half-life of 9.7 to 12.5 hours. In 15 patients with uncomplicated malaria who received a 10 mg/kg oral dose of quinine sulfate, the mean total clearance of quinine was slower (approximately 0.09 L/h/kg) during the acute phase of the infection, and faster (approximately 0.16 L/h/kg) during the recovery or convalescent phase. Extracorporeal Elimination: Administration of multiple-dose activated charcoal (50 grams administered 4 hours after quinine dosing followed by 3 further doses over the next 12 hours) decreased the mean quinine elimination half-life from 8.2 to 4.6 hours, and increased the mean quinine clearance by 56% (from 11.8 L/h to 18.4 L/h) in 7 healthy adult subjects who received a single oral 600 mg dose of quinine sulfate. Likewise, in 5 symptomatic patients with acute quinine poisoning who received multiple-dose activated charcoal (50 grams every 4 hours), the mean quinine elimination half-life was shortened to 8.1 hours in comparison to a half-life of approximately 26 hours in patients who did not receive activated charcoal [see OVERDOSAGE ( 10 ) ] . In 6 patients with quinine poisoning, forced acid diuresis did not change the half-life of quinine elimination (25.1 ± 4.6 hours vs. 26.5 ± 5.8 hours), or the amount of unchanged quinine recovered in the urine, in comparison to 8 patients not treated in this manner [see OVERDOSAGE ( 10 )] . Specific Populations Pediatric Patients: The pharmacokinetics of quinine in children (1.5 to 12 years old) with uncomplicated P. falciparum malaria appear to be similar to that seen in adults with uncomplicated malaria. Furthermore, as seen in adults, the mean total clearance and the volume of distribution of quinine were reduced in pediatric patients with malaria as compared to the healthy pediatric controls. Table 2 below provides a comparison of the mean ± SD pharmacokinetic parameters of quinine in pediatric patients vs. healthy pediatric controls. TABLE 2 Quinine Pharmacokinetic Parameters Following the First 10 mg/kg Quinine Sulfate Oral Dose in Healthy Pediatric Controls and Pediatric Patients with Acute Uncomplicated P. falciparum Malaria Healthy Pediatric Controls age 1.5 to 12 years ( N = 5 ) Mean ± SD P . falciparum Malaria Pediatric Patients ( N = 15 ) Mean ± SD T m a x (h) 2.0 4.0 C m a x (mcg/mL) 3.4 ± 1.18 7.5 ± 1.1 Half-life (h) 3.2 ± 0.3 12.1 ± 1.4 Total CL (L/h/kg) 0.30 ± 0.04 0.06 ± 0.01 Vd (L/kg) 1.43 ± 0.18 0.87 ± 0.12 Geriatric Patients: Following a single oral dose of 600 mg quinine sulfate, the mean AUC was about 38% higher in 8 healthy elderly subjects (65 to 78 years old) than in 12 younger subjects (20 to 35 years old). The mean T max and C max were similar in elderly and younger subjects after a single oral dose of quinine sulfate 600 mg. The mean oral clearance of quinine was significantly decreased, and the mean elimination half-life was significantly increased in elderly subjects compared with younger subjects (0.06 vs. 0.08 L/h/kg, and 18.4 hours vs. 10.5 hours, respectively). Although there was no significant difference in the renal clearance of quinine between the two age groups, elderly subjects excreted a larger proportion of the dose in urine as unchanged drug than younger subjects (16.6% vs. 11.2%). After a single 648 mg dose or at steady state, following quinine sulfate 648 mg given three times daily for 7 days, no difference in the rate and extent of absorption or clearance of quinine was seen between 13 elderly subjects (65 to 78 years old) and 14 young subjects (20 to 39 years old). The mean elimination half-life was 20% longer in the elderly subjects (24.0 hours) than in younger subjects (20.0 hours). The steady state C max (±SD) and AUC 0-8 (±SD) for healthy volunteers are 6.8 ± 1.24 mcg/mL and 48.8 ± 9.15 mcg*h/mL, respectively, following 7 days of oral quinine sulfate 648 mg three times daily. The steady state pharmacokinetic parameters in healthy elderly subjects were similar to the pharmacokinetic parameters in healthy young subjects. Renal Impairment : Following a single oral 600 mg dose of quinine sulfate in otherwise healthy subjects with severe chronic renal failure not receiving any form of dialysis (mean serum creatinine = 9.6 mg/dL), the median AUC was higher by 195% and the median C max was higher by 79% than in subjects with normal renal function (mean serum creatinine = 1 mg/dL). The mean plasma half-life in subjects with severe chronic renal impairment was prolonged to 26 hours compared to 9.7 hours in the healthy controls. Computer assisted modeling and simulation indicates that in patients with malaria and severe chronic renal failure, a dosage regimen consisting of one loading dose of 648 mg quinine sulfate capsules followed 12 hours later by a maintenance dosing regimen of 324 mg every 12 hours will provide adequate systemic exposure to quinine [see DOSAGE AND ADMINISTRATION ( 2.2 )] . The effects of mild and moderate renal impairment on the pharmacokinetics and safety of quinine sulfate are not known. Negligible to minimal amounts of circulating quinine in the blood are removed by hemodialysis or hemofiltration. In subjects with chronic renal failure (CRF) on hemodialysis, only about 6.5% of quinine is removed in 1 hour. Plasma quinine concentrations do not change during or shortly after hemofiltration in subjects with CRF [see OVERDOSAGE ( 10 )] . Hepatic Impairment: In otherwise healthy subjects with mild hepatic impairment (Child-Pugh A; N=10), who received a single 500 mg dose of quinine sulfate, there was no significant difference in quinine pharmacokinetic parameters or exposure to the primary metabolite, 3-hydroxyquinine as compared to healthy controls (N=10). In otherwise healthy subjects with moderate hepatic impairment (Child-Pugh B; N=9) who received a single oral 600 mg dose of quinine sulfate, the mean AUC increased by 55% without a significant change in mean Cmax, as compared to healthy volunteer controls (N=6). In subjects with hepatitis, the absorption of quinine was prolonged, the elimination half-life was increased, the apparent volume of distribution was higher, but there was no significant difference in weight-adjusted clearance. Therefore, in patients with mild to moderate hepatic impairment, dosage adjustment is not needed, but patients should be monitored closely for adverse effects of quinine [see USE IN SPECIFIC POPULATIONS ( 8.7 )] . In subjects with severe hepatic impairment (Child-Pugh C; N=10), quinine oral clearance (CL/F) was reduced as was formation of the primary 3-hydroxyquinine metabolite. Volume of distribution (Vd/F) was higher and the plasma elimination half-life was increased. Therefore, quinine is not indicated in this population and alternate therapy should be administered [see DOSAGE AND ADMINISTRATION ( 2.3 )] . 12.4 Microbiology Mechanism of Action Quinine inhibits nucleic acid synthesis, protein synthesis, and glycolysis in Plasmodium falciparum and can bind with hemazoin in parasitized erythrocytes. However, the precise mechanism of the antimalarial activity of quinine sulfate is not completely understood. Activity In Vitro and In Vivo Quinine sulfate acts primarily on the blood schizont form of P. falciparum. It is not gametocidal and has little effect on the sporozoite or pre-erythrocytic forms. Drug Resistance Strains of P. falciparum with decreased susceptibility to quinine can be selected in vivo . P. falciparum malaria that is clinically resistant to quinine has been reported in some areas of South America, Southeast Asia, and Bangladesh.

20231031

11

3 DOSAGE FORMS AND STRENGTHS 324 mg size "0" capsules with clear transparent cap and clear transparent body imprinted with "LU" on cap and "Y51" on body in black ink, containing white to off white powder ( 3 ). 324 mg size "0" capsules with clear transparent cap and clear transparent body imprinted with "LU" on cap and "Y51" on body in black ink, containing white to off white powder.

QUININE SULFATE QUININE SULFATE QUININE SULFATE QUININE FERROSOFERRIC OXIDE GELATIN MAGNESIUM STEARATE POTASSIUM HYDROXIDE PROPYLENE GLYCOL SHELLAC SODIUM LAURYL SULFATE STARCH, CORN TALC Clear Transparent Cap;Clear Transparent Body Capsule LU;Y51

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies of quinine have not been conducted. Mutagenesis Genotoxicity studies of quinine were positive in the Ames bacterial mutation assay with metabolic activation and in the sister chromatid exchange assay in mice. The sex-linked recessive lethal test performed in Drosophila , the in vivo mouse micronucleus assay, and the chromosomal aberration assay in mice and Chinese hamsters were negative. Impairment of Fertility Published studies indicate that quinine produces testicular toxicity in mice at a single intraperitoneal dose of 300 mg/kg corresponding to a dose of approximately 0.75 times the maximum recommended human dose (MRHD; 32 mg/kg/day) and in rats at an intramuscular dose of 10 mg/kg/day, 5 days/week, for 8 weeks corresponding to a daily dose of approximately 0.05 times the MRHD based on body surface area (BSA) comparisons. The findings include atrophy or degeneration of the seminiferous tubules, decreased sperm count and motility, and decreased testosterone levels in the serum and testes. There was no effect on testes weight in studies of oral doses of up to 500 mg/kg/day in mice and 700 mg/kg/day in rats (approximately 1.2 and 3.5 times the MRHD respectively based on BSA comparisons). In a published study in 5 men receiving 600 mg of quinine TID for one week, sperm motility was decreased and percent sperm with abnormal morphology was increased; sperm count and serum testosterone were unaffected.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies of quinine have not been conducted. Mutagenesis Genotoxicity studies of quinine were positive in the Ames bacterial mutation assay with metabolic activation and in the sister chromatid exchange assay in mice. The sex-linked recessive lethal test performed in Drosophila , the in vivo mouse micronucleus assay, and the chromosomal aberration assay in mice and Chinese hamsters were negative. Impairment of Fertility Published studies indicate that quinine produces testicular toxicity in mice at a single intraperitoneal dose of 300 mg/kg corresponding to a dose of approximately 0.75 times the maximum recommended human dose (MRHD; 32 mg/kg/day) and in rats at an intramuscular dose of 10 mg/kg/day, 5 days/week, for 8 weeks corresponding to a daily dose of approximately 0.05 times the MRHD based on body surface area (BSA) comparisons. The findings include atrophy or degeneration of the seminiferous tubules, decreased sperm count and motility, and decreased testosterone levels in the serum and testes. There was no effect on testes weight in studies of oral doses of up to 500 mg/kg/day in mice and 700 mg/kg/day in rats (approximately 1.2 and 3.5 times the MRHD respectively based on BSA comparisons). In a published study in 5 men receiving 600 mg of quinine TID for one week, sperm motility was decreased and percent sperm with abnormal morphology was increased; sperm count and serum testosterone were unaffected.

ANDA203112

QUININE SULFATE

QUININE SULFATE

68180-560

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Quinine Sulfate Capsules USP Rx Only 324 mg NDC-68180-560-06 30 Capsules 1

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labelling (Medication Guide) 17.1 Dosing Instructions Patients should be instructed to: Take all of the medication as directed. Take no more of the medication than the amount prescribed. Take with food to minimize possible gastrointestinal irritation. If a dose is missed, patients should also be instructed not to double the next dose. If more than 4 hours has elapsed since the missed dose, the patient should wait and take the next dose as previously scheduled. Manufactured for: Lupin Pharmaceuticals, Inc. Baltimore, Maryland 21202 United States. Manufactured by: Lupin Limited Goa 403 722 INDIA. April 2015 ID#: 229595

MEDICATION GUIDE Quinine Sulfate Capsules USP (Kwye' nine sul' fate) Read the Medication Guide that comes with quinine sulfate capsules before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. You and your healthcare provider should talk about quinine sulfate capsules when you start taking it and at regular checkups. Quinine sulfate capsules are not approved for the treatment of night-time leg cramps. What is the most important information I should know about quinine sulfate capsules? Quinine sulfate capsules used to treat or prevent leg cramps may cause serious side effects or even death. Quinine sulfate capsules may cause your blood cell (platelet) count to drop causing serious bleeding problems. In some people, serious kidney problems can happen. Quinine sulfate capsules may cause problems with your heart rhythm that can lead to death. Quinine sulfate capsules may cause serious allergic reactions. Call your healthcare provider right away if you have: easy bruising severe nose bleed blood in urine or stool bleeding gums appearance of unusual purple, brown or red spots on your skin (bleeding under your skin) rash hives severe itching severe flushing swelling of your face trouble breathing chest pain rapid heartbeat irregular heart rhythm weakness sweating nervousness Taking quinine sulfate capsules with some other medicines can increase the chance of serious side effects. Tell your health care provider if you take any other medicines. Certain medicines can cause the blood levels of quinine sulfate to be too high or too low in your body. It is important for you to tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Quinine sulfate capsules and other medicines may affect each other causing serious side effects or death. Even medicines that you may take for a short period of time, such as antibiotics, can mix in your blood with quinine sulfate and cause serious side effects or death. Do not start taking a new medicine without telling your healthcare provider or pharmacist. What are quinine sulfate capsules? Quinine sulfate capsule is a prescription medication used to treat malaria (uncomplicated) caused by the parasite Plasmodium falciparum. Quinine sulfate capsules are Not approved to: Prevent malaria Treat severe or complicated malaria Prevent or treat night-time leg cramps It is not known if quinine sulfate capsules are safe and works in children younger than 16 years old. Who should not take quinine sulfate capsules? Do not take quinine sulfate capsules if you have: certain heart rhythm problems (atrial fibrillation) or abnormal electrocardiogram (ECG) (QT prolongation). low levels of an enzyme called Glucose-6-phosphate dehydrogenase (G6PD). an autoimmune disease (myasthenia gravis) that leads to muscle weakness. had allergic reactions to quinine, quinidine, or mefloquine (Lariam ® ). had serious side effects to quinine, such as low platelets, which are necessary for your blood to clot. an inflammation of the nerve important for vision (optic neuritis). What should I tell my healthcare provider before starting quinine sulfate capsules? Before you take quinine sulfate capsules, tell your health-care provider if you: Have heart problems. Have kidney problems. Have liver problems. Have any other medical condition. Are pregnant or could be pregnant. Treatment of malaria is important because it can be a serious disease for a pregnant woman and her unborn baby. Your healthcare provider can tell you more about the benefits and risks of taking this medication during pregnancy. Low blood sugar (hypoglycemia) can be seen in pregnant women while taking quinine sulfate capsules. This can include sweating, weakness, nausea, vomiting, or confusion. You and your healthcare provider can decide if quinine sulfate capsules are right for you. Are breast-feeding. Small amounts of quinine sulfate can pass into your breast milk. You and your healthcare provider can decide if you should breastfeed while taking quinine sulfate capsules. Tell your healthcare provider about all the medicines you take, including prescription medicines, vitamins and herbal supplements. How should I take quinine sulfate capsules? Take quinine sulfate capsules USP exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how many quinine sulfate capsules to take and when to take them. To lower the chance of stomach upset, take quinine sulfate capsules with food . Finish all the quinine sulfate capsules that is prescribed even if you feel better. Do not stop taking the medication without talking to your healthcare provider. Do not take more than the amount prescribed. Do not take more than 2 capsules at one time or more than 3 doses in one day. If you take more than the prescribed dose, call your healthcare provider right away. If you forget to take quinine sulfate capsules, do not double the next dose. If it has been more than 4 hours since the missed dose, just wait and take the regular dose at the next scheduled time. Call your healthcare provider if you are not sure what to do. If you take too much quinine sulfate capsules, call your healthcare provider or go to the nearest emergency room right away. Call your healthcare provider right away if: If you feel worse, or if you do not start feeling better within 1 or 2 days of starting to take quinine sulfate capsules. If your fever comes back after finishing treatment with quinine sulfate capsules. What are the possible side effects of quinine sulfate capsules? Quinine sulfate capsules may cause serious side effects. See "What is the most important information I should know about quinine sulfate capsules " section. Low blood sugar (hypoglycemia). This can include sweating, weakness, nausea, vomiting, or confusion. Common side effects with quinine sulfate capsules include: headache sweating flushing nausea ringing in your ears diarrhea deafness hearing loss dizziness (vertigo) blurred vision changes in how you see color vomiting stomach pain blindness Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of quinine sulfate capsules. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store quinine sulfate capsules? Keep the capsules in a tightly closed container. Do not refrigerate or freeze. Store at 15° to 30°C (59° to 86°F). Keep quinine sulfate capsules and all medicines out of the reach of children. General Information about quinine sulfate capsules Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use quinine sulfate capsules for a condition for which it was not prescribed. Do not give quinine sulfate capsules to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about quinine sulfate capsules. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about quinine sulfate capsules that is written for healthcare professionals. For more information, go to www.lupinpharmaceuticals.com or call 1-800-399-2561. What are the ingredients in quinine sulfate capsules? Active Ingredients: Quinine Sulfate USP Inactive Ingredients: Black Iron Oxide, Corn Starch, Gelatin, Magnesium Stearate, Potassium Hydroxide, Propylene Glycol, Shellac, Sodium Lauryl Sulfate and Talc. This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured for: Lupin Pharmaceuticals, Inc. Baltimore, Maryland 21202 United States. Manufactured by: Lupin Limited Goa 403 722 INDIA. April 2015 ID#: 229596

14 CLINICAL STUDIES Quinine has been used worldwide for hundreds of years in the treatment of malaria. Thorough searches of the published literature identified over 1300 references to the treatment of malaria with quinine, and from these, 21 randomized, active-controlled studies were identified which evaluated oral quinine monotherapy or combination therapy for treatment of uncomplicated P. falciparum malaria. Over 2900 patients from malaria-endemic areas were enrolled in these studies, and more than 1400 patients received oral quinine. The following conclusions were drawn from review of these studies: In areas where multi-drug resistance of P. falciparum is increasing, such as Southeast Asia, cure rates with 7 days of oral quinine monotherapy were at least 80%; while cure rates for 7 days of oral quinine combined with an antimicrobial agent (tetracycline or clindamycin) were greater than 90%. In areas where multi-drug resistance of the parasite was not as widespread, cure rates with 7 days of quinine monotherapy ranged from 86 to 100%. Cure was defined as initial clearing of parasitemia within 7 days without recrudescence by day 28 after treatment initiation. P. falciparum malaria that is clinically resistant to quinine has been reported in some areas of South America, Southeast Asia, and Bangladesh, and quinine may not be as effective in those areas. Completion of a 7-day oral quinine treatment regimen may be limited by drug intolerance, and shorter courses (3 days) of quinine combination therapy have been used. However, the published data from randomized, controlled clinical trials for shorter regimens of oral quinine in conjunction with tetracycline, doxycycline, or clindamycin for treatment of uncomplicated P. falciparum malaria is limited, and these shorter course combination regimens may not be as effective as the longer regimens.

8 USE IN SPECIFIC POPULATIONS Renal impairment: Reduce dose and dosing frequency for patients with severe chronic renal impairment ( 2.2 , 8.6 , 12.3 ). Hepatic impairment: Closely monitor for adverse events. Quinine should not be administered in patients with severe (Child-Pugh C) hepatic impairment ( 2.3 , 8.7 , 12.3 ). Pregnancy: Based on animal data may cause fetal harm. Use only if the potential benefit justifies the risk ( 8.1 ). Nursing Mothers: Exercise caution when administering to a nursing woman ( 8.3 ). 8.1 Pregnancy Pregnancy Category C There are extensive published data but few well-controlled studies of quinine sulfate in pregnant women. Published data on over 1,000 pregnancy exposures to quinine did not show an increase in teratogenic effects over the background rate in the general population; however, the majority of these exposures were not in the first trimester. In developmental and reproductive toxicity studies, central nervous system (CNS) and ear abnormalities and increased fetal deaths occurred in some species when pregnant animals received quinine at doses about 1 to 4 times the human clinical dose. Quinine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. P. falciparum malaria carries a higher risk of morbidity and mortality in pregnant women than in the general population. Pregnant women with P. falciparum malaria have an increased incidence of fetal loss (including spontaneous abortion and stillbirth), preterm labor and delivery, intrauterine growth retardation, low birth weight, and maternal death. Therefore, treatment of malaria in pregnancy is important. Hypoglycemia, due to increased pancreatic secretion of insulin, has been associated with quinine use, particularly in pregnant women. Quinine crosses the placenta with measurable blood concentrations in the fetus. In 8 women who delivered live infants 1 to 6 days after starting quinine therapy, umbilical cord plasma quinine concentrations were between 1.0 and 4.6 mg/L (mean 2.4 mg/L) and the mean (±SD) ratio of cord plasma to maternal plasma quinine concentrations was 0.32 ± 0.14. Quinine levels in the fetus may not be therapeutic. If congenital malaria is suspected after delivery, the infant should be evaluated and treated appropriately. A study from Thailand (1999) of women with P. falciparum malaria who were treated with oral quinine sulfate 10 mg/kg 3 times daily for 7 days at anytime in pregnancy reported no significant difference in the rate of stillbirths at >28 weeks of gestation in women treated with quinine (10 of 633 women [1.6%]) as compared with a control group without malaria or exposure to antimalarial drugs during pregnancy (40 of 2201 women [1.8%]). The overall rate of congenital malformations (9 of 633 offspring [1.4%]) was not different for women who were treated with quinine sulfate compared with the control group (38 of 2201 offspring [1.7%]). The spontaneous abortion rate was higher in the control group (10.9%) than in women treated with quinine sulfate (3.5%) [OR = 3.1; 95% CI 2.1 to 4.7]. An epidemiologic survey that included 104 mother-child pairs exposed to quinine during the first 4 months of pregnancy, found no increased risk of structural birth defects was seen (2 fetal malformations [1.9%]). Rare and isolated case reports describe deafness and optic nerve hypoplasia in children exposed in utero due to maternal ingestion of high doses of quinine. In animal developmental studies conducted in multiple animal species, pregnant animals received quinine by the subcutaneous or intramuscular route at dose levels similar to the maximum recommended human dose (MRHD; 32 mg/kg/day) based on body surface area (BSA) comparisons. There were increases in fetal death in utero in rabbits at maternal doses ≥ 100 mg/kg/day and in dogs at ≥ 15 mg/kg/day corresponding to dose levels approximately 0.5 and 0.25 times the MRHD respectively based on BSA comparisons. Rabbit offspring had increased rates of degenerated auditory nerve and spiral ganglion and increased rates of CNS anomalies such as anencephaly and microcephaly at a dose of 130 mg/kg/day corresponding to a maternal dose approximately 1.3 times the MRHD based on BSA comparison. Guinea pig offspring had increased rates of hemorrhage and mitochondrial change in the cochlea at maternal doses of 200 mg/kg corresponding to a dose level of approximately 1.4 times the MRHD based on BSA comparison. There were no teratogenic findings in rats at maternal doses up to 300 mg/kg/day and in monkeys at doses up to 200 mg/kg/day corresponding to doses approximately 1 and 2 times the MRHD respectively based on BSA comparisons. In a pre- postnatal study in rats, an estimated oral dose of quinine sulfate of 20 mg/kg/day corresponding to approximately 0.1 times the MRHD based on BSA comparison resulted in offspring with impaired growth, lower body weights at birth and during the lactation period, and delayed physical development of teeth eruption and eye opening during the lactation period. 8.2 Labor and Delivery There is no evidence that quinine causes uterine contractions at the doses recommended for the treatment of malaria. In doses several-times higher than those used to treat malaria, quinine may stimulate the pregnant uterus. 8.3 Nursing Mothers There is limited information on the safety of quinine in breastfed infants. No toxicity was reported in infants in a single study where oral quinine sulfate (10 mg/kg every 8 hours for 1 to 10 days) was administered to 25 lactating women. It is estimated from this study that breastfed infants would receive less than 2 to 3 mg per day of quinine base (< 0.4% of the maternal dose) via breast milk [see CLINICAL PHARMACOLOGY ( 12.3 )] . Although quinine is generally considered compatible with breastfeeding, the risks and benefits to infant and mother should be assessed. Caution should be exercised when administered to a nursing woman. If malaria is suspected in the infant, appropriate evaluation and treatment should be provided. Plasma quinine levels may not be therapeutic in infants of nursing mothers receiving quinine sulfate. 8.4 Pediatric Use The safety and efficacy of quinine sulfate in pediatric patients under the age of 16 has not been established. 8.5 Geriatric Use Clinical studies of quinine sulfate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond to treatment differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. 8.6 Renal Impairment Clearance of quinine is decreased in patients with severe chronic renal failure. The dosage and dosing frequency should be reduced [see DOSAGE AND ADMINISTRATION ( 2.2 ), CLINICAL PHARMACOLOGY ( 12.3 )] . 8.7 Hepatic Impairment In patients with severe hepatic impairment (Child-Pugh C), quinine oral clearance (CL/F) is decreased, volume of distribution (Vd/F) is increased, and half-life is prolonged, relative to subjects with normal liver function. Therefore, quinine is not indicated in patients with severe hepatic impairment and alternate therapy should be administered [see DOSAGE AND ADMINISTRATION ( 2.3 ) and CLINICAL PHARMACOLOGY ( 12.3 )] . Close monitoring is recommended for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, as exposure to quinine may be increased relative to subjects with normal liver function [see CLINICAL PHARMACOLOGY ( 12.3 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Quinine sulfate capsules USP, 324 mg are available as size "0" capsules with clear transparent cap and clear transparent body imprinted with "LU" on cap and "Y51" on body in black ink, containing white to off white powder: Bottles of 30 NDC 68180-560-06 Bottles of 100 NDC 68180-560-01 Bottles of 500 NDC 68180-560-02 Bottles of 1000 NDC 68180-560-03 16.2 Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature] Dispense in a tight container as defined in the USP.

WARNING: HEMATOLOGIC REACTIONS [see FULL PRESCRIBING INFORMATION for complete boxed warning] Quinine sulfate capsules use for the treatment or prevention of nocturnal leg cramps may result in serious and life-threatening hematologic reactions, including thrombocytopenia and hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP). Chronic renal impairment associated with the development of TTP has been reported. The risk associated with quinine sulfate capsules use in the absence of evidence of its effectiveness in the treatment or prevention of nocturnal leg cramps outweighs any potential benefit ( 5.1 ) . WARNING: HEMATOLOGIC REACTIONS Quinine sulfate capsules use for the treatment or prevention of nocturnal leg cramps may result in serious and life-threatening hematologic reactions, including thrombocytopenia and hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP). Chronic renal impairment associated with the development of TTP has been reported. The risk associated with quinine sulfate capsules use in the absence of evidence of its effectiveness in the treatment or prevention of nocturnal leg cramps outweighs any potential benefit [see WARNINGS AND PRECAUTIONS ( 5.1 )].